PROJECT SUMMARY/ABSTRACT The NIH-NIDCR-funded Sjgren?s International Collaborative Clinical Alliance (SICCA) was established in 2003 to improve the understanding, diagnosis and treatment of patients with Sjgren?s syndrome (SS) by 1) developing/validating standardized classification criteria for SS; and 2) developing a longitudinal data and biospecimen repository that could be used by the research community for future epidemiologic, pathogenesis, and genetic studies of SS. Using rigorous study design and standardized data and specimen collection protocols, SICCA investigators from nine leading academic research groups across the globe assembled a unique biorepository from a cohort of 3,514 participants with extremely well characterized phenotypic data (with follow-up data/specimens on 771). Multiple deliverables were achieved including 1) the development and validation of classification criteria for SS provisionally approved by the American College of Rheumatology (ACR) in 2011 (followed by the development and validation, in collaboration with the European League Against Rheumatism (EULAR) SS Taskforce, of a set of classification criteria approved by ACR and EULAR in 2016); 2) a genome-wide association study that highlighted the genetic heterogeneity of SS according to ancestry, and established a unique genetic repository for SS available for public use through dbGAP; and 3) a dissemination plan, which has yielded important new findings regarding the SS phenotype. In response to PAR-17-154, our proposal leverages unique NIDCR-funded resources by utilizing existing infrastructure and an expanded team with high level expertise, and is poised to exploit recent explosive growth in immunology, genomics and epigenetics to better understand the pathogenesis of SS and identify therapeutic pathways, and new biomarkers. We propose to 1) assemble an international external scientific advisory group to guide us in continuing a targeted dissemination plan, and 2) collaborate with UCSF and UC Berkeley scientists, further exploring transcriptomics and epigenetics in SS. Thus, we propose to enhance the SICCA biorepository/registry by generating genome-wide DNA methylation and whole-genome sequencing of single- cell mRNA, bulk mRNA, and miRNA that will enable high impact studies of underlying biologic pathways of SS both by our team and through an expanded dissemination plan that can leverage these enhanced data sets. Specifically, we aim to 1) Explore transcriptomic diversity across subsets of SICCA participants with well characterized epigenetic and genetic profiles, and across cell and tissue types (PBMCs, labial salivary glands); 2) Explore correlations between these omics profiles and signs of severe disease manifestations, including presence of germinal-cell-formations and focal lymphocytic sialadenitis with a high focus score, high IgG, and hypocomplementemia; and 3) Characterize temporal changes (2-3 years) in omics profiles. While traditional phenotypic features of SS are relatively stable, we hypothesize that omics profiles may be more dynamic, providing insight into biologic processes associated with disease progression and outcome.